1994 20mm aspirin “ikb concentrations in the salicylate cell extracts were the same as in control...

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1994

20mM aspirin“IkB concentrations in the salicylatecell extracts were the same as in controlwhereas IkB was reduced in activated cellswithout salicylate”

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Not seeing the same inhibition profile as other antiinflammatory agents.

CREBNFkB NFkB

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Other antiinflammatory drugs inhibit prostaglandin synthesisbut they do not alter IKK activity

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Inhibition of IKK activity is unique to ASA and Sal

Only IKKbeta inhibited

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Effective [ASA] 1-5mMOther pathways

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IKK SS->EE mutations (constitutively active)

Not upstream of IKK

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Recombinant IKK beta - same trend as “in vivo”

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“in vivo” “in vitro”

80uM 30-50uM

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Suggest not covalently bound

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Inhibition of kinase activity [] dept. of aspirin

“preincubation”

How does this relate to cancer?

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Many Faces of Ubiquitin - Deubiquitinating Enzymes

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Familial Cylindromatosis(benign tumors)

Usually on forehead and scalp

Dominantly inheriteddue to loss of the tumor suppressor:

CYLD

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Used siRNA to knockdown expression of CYLD

PMA (phorbol ester) stimulates NFkB via IkBalpha degradation

When “KD” CYLD - increased proliferation

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16hours later

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